Skip to main content
SpringerLink
Log in

R-GEM-Lenalidomide versus R-GEM-P as second-line treatment of diffuse large B-cell lymphoma: results of the UK NRCI phase II randomised LEGEND trial

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

This article has been updated

Abstract

Outcome of patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) remains poor, highlighting the need for novel treatment approaches. The multicentre randomised phase II LEGEND trial evaluated lenalidomide in combination with rituximab, methylprednisolone and gemcitabine (R-GEM-L) vs. standard R-GEM-P as second-line treatment of DLBCL. The study closed early to recruitment after the planned interim analysis failed to demonstrate a complete response (CR) rate of ≥ 40% in either arm. Among 34 evaluable patients, 7/18 (38.9%) achieved CR with R-GEM-L and 3/16 (18.8%) with R-GEM-P. Median event-free and overall survival was 3.5/3.8 months and 10.8/8.3 months for R-GEM-L and R-GEM-P, respectively. The incidence of grade ≥ 3 toxicities was 52% in R-GEM-L and 83% in R-GEM-P. Efficacy and tolerability of R-GEM-L seem comparable with R-GEM-P and other standard salvage therapies, but a stringent design led to early trial closure. Combination of lenalidomide with gemcitabine-based regimens should be further evaluated in r/r DLBCL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Change history

  • 30 December 2020

    The missing ESM file was inserted.

References

  1. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, van den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242

    Article  CAS  Google Scholar 

  2. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M, German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) (2008) Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 9:105–116

    Article  CAS  Google Scholar 

  3. Pfreundschuh M, Kuhnt E, Trümper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully Brown P, Stahel R, Milpied N, López-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N, MabThera International Trial (MInT) Group (2011) CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12:1013–1022

    Article  CAS  Google Scholar 

  4. Tilly H et al (2015) Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26(Suppl 5):v116–v125

    Article  Google Scholar 

  5. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N (2010) Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28:4184–4190

    Article  Google Scholar 

  6. Barton S, Hawkes EA, Cunningham D, Peckitt C, Chua S, Wotherspoon A, Attygalle A, Horwich A, Potter M, Ethell M, Dearden C, Gleeson M, Chau I (2015) Rituximab, gemcitabine, cisplatin and methylprednisolone (R-GEM-P) is an effective regimen in relapsed diffuse large B-cell lymphoma. Eur J Haematol 94:219–226

    Article  CAS  Google Scholar 

  7. Crump M, Kuruvilla J, Couban S, MacDonald D, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE (2014) Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol 32:3490–3496

    Article  CAS  Google Scholar 

  8. Van Imhoff GW et al (2017) Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol 35:544–551

    Article  Google Scholar 

  9. Lerner RE, Thomas W, DeFor TE, Weisdorf DJ, Burns LJ (2007) The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell non-Hodgkin’s lymphoma in second complete or partial remission. Biol Blood Marrow Transplant 13:486–492

    Article  Google Scholar 

  10. Martin A et al (2008) R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica 93:1829–1836

    Article  CAS  Google Scholar 

  11. Wiernik PH, Lossos IS, Tuscano JM, Justice G, Vose JM, Cole CE, Lam W, McBride K, Wride K, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Habermann TM (2008) Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol 26:4952–4957

    Article  Google Scholar 

  12. Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, Bouabdallah R, Haioun C, Tilly H, Guo P, Pietronigro D, Ervin-Haynes AL, Czuczman MS (2011) An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol 22:1622–1627

    Article  CAS  Google Scholar 

  13. Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID (2017) A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator’s choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res 23:4127–4137

    Article  CAS  Google Scholar 

  14. Zinzani PL et al (2011) Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk 11:462–466

    Article  CAS  Google Scholar 

  15. Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS, Hagemeister F, Fanale M, Oki Y, Pro B, Shah J, Thomas S, Younes A, Hosing C, Zhang L, Newberry KJ, Desai M, Cheng N, Badillo M, Bejarano M, Chen Y, Young KH, Champlin R, Kwak L, Fayad L (2013) Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia 27:1902–1909

    Article  CAS  Google Scholar 

  16. Vitolo U, Chiappella A, Franceschetti S, Carella AM, Baldi I, Inghirami G, Spina M, Pavone V, Ladetto M, Liberati AM, Molinari AL, Zinzani P, Salvi F, Fattori PP, Zaccaria A, Dreyling M, Botto B, Castellino A, Congiu A, Gaudiano M, Zanni M, Ciccone G, Gaidano G, Rossi G, Fondazione Italiana Linfomi (2014) Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial. Lancet Oncol 15:730–737

    Article  CAS  Google Scholar 

  17. Nowakowski GS, LaPlant B, Macon WR, Reeder CB, Foran JM, Nelson GD, Thompson CA, Rivera CE, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Ansell SM, Gascoyne RD, Habermann TM, Witzig TE (2015) Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J Clin Oncol 33:251–257

    Article  CAS  Google Scholar 

  18. Martín A, Redondo AM, Dlouhy I, Salar A, González-Barca E, Canales M, Montes-Moreno S, Ocio EM, López-Guillermo A, Caballero D, Spanish Group for Lymphomas and Autologous Bone Marrow (GELTAMO) (2016) Lenalidomide in combination with R-ESHAP in patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 1b study from GELTAMO group. Br J Haematol 173:245–252

    Article  CAS  Google Scholar 

  19. Feldman T, Mato AR, Chow KF, Protomastro EA, Yannotti KM, Bhattacharyya P, Yang X, Donato ML, Rowley SD, Carini C, Valentinetti M, Smith J, Gadaleta G, Bejot C, Stives S, Timberg M, Kdiry S, Pecora AL, Beaven AW, Goy A (2014) Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma. Br J Haematol 166:77–83

    Article  CAS  Google Scholar 

  20. Gribben JG, Fowler N, Morschhauser F (2015) Mechanisms of action of lenalidomide in B-cell non-Hodgkin lymphoma. J Clin Oncol 33:JCO.2014.59.5363

    Article  CAS  Google Scholar 

  21. Yang Y, Shaffer a 3rd, Emre NC, Ceribelli M, Zhang M, Wright G, Xiao W, Powell J, Platig J, Kohlhammer H, Young RM, Zhao H, Yang Y, Xu W, Buggy JJ, Balasubramanian S, Mathews LA, Shinn P, Guha R, Ferrer M, Thomas C, Waldmann TA, Staudt LM (2012) Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 21:723–737

    Article  CAS  Google Scholar 

  22. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, Pileri SA, Malik F, Macon WR, Goy A, Witzig TE, Czuczman MS (2011) Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer 117:5058–5066

    Article  CAS  Google Scholar 

  23. Thieblemont C et al (2017) Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. JCO 35:2473–2481

    Article  CAS  Google Scholar 

  24. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V, International Harmonization Project on Lymphoma (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25:579–586

    Article  Google Scholar 

  25. Scott DW, Wright GW, Williams PM, Lih CJ, Walsh W, Jaffe ES, Rosenwald A, Campo E, Chan WC, Connors JM, Smeland EB, Mottok A, Braziel RM, Ott G, Delabie J, Tubbs RR, Cook JR, Weisenburger DD, Greiner TC, Glinsmann-Gibson BJ, Fu K, Staudt LM, Gascoyne RD, Rimsza LM (2014) Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin embedded tissue. Blood 123:1214–1217

    Article  CAS  Google Scholar 

  26. Zhang LH, Kosek J, Wang M, Heise C, Schafer PH, Chopra R (2013) Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression. Br J Haematol 160:487–502

    Article  CAS  Google Scholar 

  27. Nowakowski GS, Hong F, Scott DW (2019) Addition of lenalidomide to R-CHOP (R2CHOP) improves outcome in newly diagnosed diffuse large B-cell lymphoma (DLBCL): first report of ECOG-ACRIN1412 a randomized phase 2 US Intergroup study of R2CHOP vs R-CHOP. Hematological Oncology 37–38

  28. Johnston PB, Wiseman GA, Micallef INM (2008) Positron emission tomography using F-18 fluorodeoxyglucose pre- and post-autologous stem cell transplant in non-Hodgkin’s lymphoma. Bone Marrow Transplant 41:919–925

    Article  CAS  Google Scholar 

  29. Sauter CS, Matasar MJ, Meikle J, Schoder H, Ulaner GA, Migliacci JC, Hilden P, Devlin SM, Zelenetz AD, Moskowitz CH (2015) Prognostic value of FDG-PET prior to autologous stem cell transplantation for relapsed and refractory diffuse large B-cell lymphoma. Blood 125:2579–2581

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank participating centres of the LEGEND trial, as well as patients and their families involved. The study was in part supported by a research grant from Celgene Corporation. NanoString analyses were funded by a grant from the Royal Marsden National Institute for Health Research (NIHR) Biomedical Research Centre. Site accreditation, data collation and quality control for PET imaging was performed by the UK PET Core lab. K.M.A is supported by the UCL/UCLH Biomedical Research Centre.

Funding

I.C. has received research funding from Eli-Lilly, Janssen-Cilag, Sanofi Oncology, Merck Serono, and Novartis; participated on advisory boards for Sanofi Oncology, Eli-Lilly, Bristol-Myers Squibb, Merck Sharpe Dohme (MSD), Bayer, Roche and Five Prime Therapeutics; and received honoraria from Taiho, Pfizer, Amgen and Eli-Lilly. D.C. has received research funding from Amgen, AstraZeneca, Bayer, Celgene, Medimmune, Merck Serono, Merrimack and Sanofi.

Author information

Authors and Affiliations

  1. Royal Marsden NHS Foundation Trust London and Surrey, Downs Road Sutton, Surrey, SM2 5PT, UK

    Andrea Kühnl, Clare Peckitt, Bijal Patel, Sarah Barton, Ian Chau, Ruwaida Begum, Andrew Wotherspoon, Yong Du, Imene Zerizer & David Cunningham

  2. Department of Haematology, King’s College Hospital NHS Foundation Trust, London, UK

    Andrea Kühnl

  3. University College London Hospital, London, UK

    Kirit M. Ardeshna

  4. Blackpool Victoria Hospital, Blackpool, UK

    Marian P. Macheta

  5. University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

    John Radford

  6. St James’s Hospital, Leeds, UK

    Rod Johnson

  7. Heart of England NHS Foundation Trust, Birmingham, UK

    Shankaranarayana Paneesha

  8. Wellington Blood and Cancer Centre, Wellington, New Zealand

    Sarah Barton

  9. Division of Molecular Pathology, The Institute of Cancer Research, Surrey, UK

    Nicola Valeri

Authors
  1. Andrea Kühnl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clare Peckitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bijal Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kirit M. Ardeshna
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marian P. Macheta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John Radford
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rod Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shankaranarayana Paneesha
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sarah Barton
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ian Chau
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ruwaida Begum
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nicola Valeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Andrew Wotherspoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yong Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Imene Zerizer
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. David Cunningham
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.K.: trial physician, contributed to the conduct of the study, analysed and interpreted data, and wrote the report. C.P.: trial statistician, designed the study, analysed data and contributed to writing of the report. B.P.: trial coordinator, gathered, entered and coordinated data. K.M.A, M.P.M, J.R., R.J., S.P: co-investigators, gathered and interpreted data. S.B.: contributed to the study design. I.C.: contributed to the study conduct. R.B.: trial specimen coordinator, gathered tissue for central review. N.V.: performed NanoString analyses. A.W.: trial histopathologist, performed central histopathology review. Y.D., I.Z.: trial radiologists, performed central radiology review. D.C.: chief investigator, responsible for the study conduct and final report. All authors reviewed and approved the final version of the report.

Corresponding author

Correspondence to David Cunningham.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 1.51 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kühnl, A., Peckitt, C., Patel, B. et al. R-GEM-Lenalidomide versus R-GEM-P as second-line treatment of diffuse large B-cell lymphoma: results of the UK NRCI phase II randomised LEGEND trial. Ann Hematol 99, 105–112 (2020). https://doi.org/10.1007/s00277-019-03842-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-019-03842-4

Keywords

Search

Navigation